Low-level chronic inflammation is a hallmark of aging, and is a promising target for interventions that aim to delay the aging process. An important driver of systemic inflammation is the accumulation of pro-inflammatory (M1) macrophages. M1 Macrophages mediate acute inflammatory episodes after injury or infection, but to resolve inflammation, macrophages have to polarize into and anti-inflammatory (M2) phenotype. In preliminary studies, the applicants have identified Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) as an evolutionarily conserved modulator of immune cell polarization that promotes tissue repair in flies and mice. This function of MANF is required for tissue repair after damage, and can be harnessed to promote tissue regeneration in murine disease models. The applicants further found that serum MANF levels decrease with age, and that MANF deficiency in mice results in phenotypes that are consistent with widespread systemic inflammation. Based on these data, the applicants propose that MANF is a promising, evolutionarily conserved anti-geronic protein that can be used to delay or even reverse age-associated inflammatory phenotypes. To test this hypothesis, the applicants propose studies in flies and mice, pursuing three aims: (i) to characterize the effects of MANF on aging-related phenotypes in Drosophila, (ii) to assess the role of MANF in limiting age- related inflammation in mice, and (iii) to test MANF supplementation as a potential therapy for age-related diseases. The proposed studies will introduce MANF as an immune-modulatory anti-geronic protein that can limit inflammaging and is therapeutically available. A successful outcome of this study will provide a direct avenue toward translation in pro-regenerative and anti-aging therapies.